J. Microbiol. Infect. Dis., (2024), Vol. 14(4): 146–157

Review Article

10.5455/JMID.20240728102527

A review on the therapeutic effect of phytosynthesized manganese oxide nanoparticles for the management of microbial infections

Boulaares Islam^1,2 and Derouiche Samir ^1,2*

¹Department of Cellular and Molecular Biology, Faculty of Natural Sciences and Life, University of El-Oued, El-Oued 39000, Algeria

²Laboratory of Biodiversity and Application of Biotechnology in the Agricultural Field, Faculty of Natural Sciences and Life, University of El-Oued, El-Oued 39000, Algeria

*Corresponding Author: Pr. Samir Derouiche, Department of Cellular and Molecular Biology, Faculty of natural science and life, University of Echahid Hamma Lakhdar-Eloued, El-oued 39000, Algeria. Email: dersamebio [at] gmail.com

Submitted: 28/07/2024 Accepted: 18/11/2024 Published: 31/12/2024

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ABSTRACT

Purpose: Antibiotics are drugs used to treat and prevent bacterial infections. The emergence of antibiotic resistance in bacterial strains is one of the most important problems facing global health care. There are several alternatives to get rid of antibiotic resistance, including nanoparticles, which is the subject of this study on how to use manganese oxide nanoparticles (MnO NPs) as antimicrobials with greater effectiveness and less resistance to them.

Materials and methods: There are several physical, chemical, and biological techniques for the production of nanoparticles. However, the green synthesis of nanoparticles has been developed to improve the environment and human health safety, minimize pollution, and save expenses by using plant extracts instead of industrial chemical components to reduce metal ions. Accurate and comprehensive characterization using various physicochemical techniques is crucial for ensuring biological activity, safety, and reproducibility in the production of these MnO NPs.

Results: Green synthesized MnO NPs are a promising source of new antiviral, antibacterial, and antifungal agents considering the multiplicity of its mechanism and the multiple target areas in the microbes. The MnO NPs interact directly with some biological molecules of the microbes, such as some proteins, DNA, and RNA. This reaction generates reactive oxygen species (ROS), causing damage to the membranes in the microbes. Metal nano-therapies such as MnO NPs are granted research consideration for virus, bacteria, or fungi treatment.

Conclusion: The biocompatibility achieved through green synthesis of MnO NPs suggests its possible use in several types of microbe’s infections with less risk of toxicity of these new materials.

Keywords: MnO NPs; Green synthesis; Nanobiotechnology; Microbial infections; Antibiotic resistance.

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INTRODUCTION

One of the main causes of death and disability is infectious infections (Wilson and Wilson 2021). Antimicrobial resistance is the ability of microorganisms, such as bacteria, viruses, fungi, and parasites, to survive and proliferate in the presence of medications meant to destroy them. Antimicrobial-resistant organism infections are not only hard to cure, but they also carry a constant risk of serious sickness and possibly even death (Salam et al. 2023). Antibiotics are drugs used to treat and prevent bacterial infections (Shabatina et al. 2023). The emergence of antibiotic resistance in bacterial strains is one of the most important problems facing global health care. One of the most promising methods for preventing bacterial antibiotic resistance is the use of metal nanoparticles and their oxides. Metal oxide nanoparticles (NPs) have been shown in numerous studies to possess potent antibacterial properties against both Gram-positive and Gram-negative bacterial species (Faisal et al. 2022a). Specifically, treating viral infections poses a new challenge due to the use of nanotechnology. When used as monotherapy, the clinical benefit of antiviral medications may be compromised by the incidence of drug-resistant viruses, particularly in patients who are critically ill (Kumar et al. 2019a). The number of antifungal agent types limits the availability of therapy, even if antifungal drug treatment is one of the therapies that gave rise to antifungal drug resistance. However, this issue does not seem to be the same in bacteria as antibacterial agents (Dheeb et al. 2019). Numerous investigations have shown a number of MONPs having antibiotic action (Packialakshmi et al. 2023). The secondary metabolites present in manganese nanoparticles produced through the green program exhibit potential anti-inflammatory, anti-plasmodium, anti-cancer, anti-fungal, anti-diabetic, and antibacterial properties, and they can combat a range of bacterial strains (Ramesh et al. 2021). Nanotechnology has gained considerable attention in both the scientific and technological sectors, particularly because of its diverse range of applications in fields such as biomedicine, optics, and electronics (Chetehouna et al. 2024b). In recent times, there has been a significant upswing in the use of nanotechnology in the field of medicine to combat and eradicate diseases within the human body (Boulaares et al. 2024b). Nanoparticles, which can range in size from 1 to 100 nm, are the fundamental building blocks of nanotechnology (Chetehouna et al. 2024a). Because of their excellent biosecurity, unique physical and chemical properties, and tunable structures and morphologies, manganese oxide nanomaterials and their derivatives have garnered increasing attention in the last 20 years for use in biosensing, drug/gene delivery, and tumor therapy (Ding et al. 2020). The purpose of this review is to draw attention to the advantages of MnO NPs in the treatment of various diseases caused by microbes.

Figure 1. Various methods of metal nanoparticle synthesis (Khan et al. 2022).

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METHODS

The data were collected by searching Science Direct, Google Scholar, PubMed, Scopus, Springer, and the National Center for Biotechnology Information (NCBI). The keywords used as search terms were “manganese oxide nanoparticles”, “green synthesis of nanoparticles”, “microbial infections”, “antibiotic resistance”, “anti-oxidant power of nanoparticles”, “immunomodulatory activity of nanoparticles”, “anticancer potential of nanoparticles”, “antidiabetic potential of nanoparticles”, “antibacterial activity of nanoparticles”, “antiviral activity of nanoparticles”, and “antifungal activity of nanoparticles”.

General Method of Synthesis for Metal Nanoparticles

There exist several physical, chemical, and biological techniques for the production of nanoparticles (Augustine and Hasan 2020) (Figure 1). Numerous drawbacks of the physical method include its high cost, high productivity, high energy requirements, radiation exposure, large waste generation, temperature and pressure, lower stability, high dilution, difficult size and shape tunability, and altered surface chemistry and physicochemical properties of NPs (Bloch et al. 2021). Furthermore, the majority of nanoscale metals are produced using chemical processes that have unforeseen consequences such as high energy consumption, environmental contamination, and potential health risks (Ying et al. 2022). Green synthesis of nanoparticles has been developed to improve the environment and human health safety, minimize pollution, and save expenses by using plant extracts instead of industrial chemical components to reduce metal ions (Yang et al. 2023). It has been suggested that the phytochemicals present in medicinal plants act as a renewable, biocompatible, and inexpensive source for NPs green synthesis (Thatyana et al. 2023).

Green Synthesis of MnO NPs

Recently, a new field of nanotechnology called nano-biotechnology has emerged. In this field, bioactive metabolites that have been isolated from biological organisms like plants, algae, bacteria, and fungi are used to produce nanoparticles (El-Moslamy et al. 2023). The biological process of oxidation and reduction by plant phytochemicals or microbial enzymes is used in biological synthesis (Chakraborty et al. 2022). Compared to fungi and bacteria, which require a lengthy incubation period due to the presence of water-soluble phytochemicals, plants perform metal ion reduction more quickly (Mohamed El Shafey 2020). Among these green biological approaches, plant-based NP green synthesis is now considered the gold standard because of its versatility and ease of usage (Hano and Abbasi 2022). Nonetheless, due to their decreased toxicity, MnO NPs have become more significant in the synthesis and production processes (Khan et al. 2020). The green synthesis of MnO NPs may be carried out at room temperature and normal pressure and has the advantages of being non-toxic, environmentally friendly, clean, and inexpensive when employing raw materials, fruits and vegetables, plant extracts, microbes, and fungi (Nie et al. 2022). The green synthesis mechanism of MnO NPs is shown in (Figure 2).

Figure 2. Green synthesis mechanism of MnO NPs (Zhang et al. 2023).

Green Synthesis of MnO NPs Using Plant Extract

Among these green bisological approaches, plant-based NP green synthesis is now considered the gold standard because of its versatility and ease of usage (Hano and Abbasi 2022). In addition, other plant parts, including the leaves, fruits, and stems, as well as their extracts, have been utilized to generate metal nanoparticles (Chopra et al. 2022). It has been demonstrated that the phytochemical components found in plants, such as terpenoids, alkaloids, polyphenols, and flavonoids, cause metal ions to the reduced and eventually result in metal nanoparticles (Lu et al. 2022). Visual monitoring of the MnO₂ NP synthesis was conducted by observing the color shift that resulted from the addition of a precursor to the leaf extraction process (Faisal et al. 2022b). Various parameters, including pH, temperature, duration of contact, concentration of metal salts, and phytochemical composition of plant leaf particles, influence the quality, stability, quantity, and pace of production of nanoparticles (Mohamed El Shafey 2020).

Different types of nanoparticles have been continuously synthesized using different plants such as manganese oxide nanoparticles (MnO NPs) from Ocimum basilicum L. leaves (Boulaares et al. 2024c), selenium oxide nanoparticles (SeO NPs) from Sonchus maritimus leaves (Chetehouna et al. 2023), magnesium oxide nanoparticles (MgO NPs) from Ocimum basilicum L. leaves (Derouiche et al. 2020), copper oxide nanoparticles (CuO NPs) from Portulaca oleracea L. leaves (Atoussi et al. 2020), zinc oxide nanoparticles (ZnO NPs) from Spinacia oleracea leaves (Djouadi and Derouiche 2021). The process for producing MnO NPs from plant extract is depicted in (Figure 3), and Table 1 lists the many plants that can produce MnO NPs.

Figure 3. Green synthesis of MnO NPs using extract of various plant parts (Rónavári et al. 2021).

Analytical Characterization Technics of MnO NPs

Biological activity, safety, and reproducibility in the production of these NPs depend on accurate and comprehensive characterization. Ultraviolet-visible spectroscopy (UV-Vis), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffractometer (XRD) are only some of the many physicochemical techniques applied to precisely analyze the synthesized NPs for this purpose (Hano and Abbasi 2022). One of the most commonly employed techniques for characterizing nanoparticles is UV-Vis, which gives users accurate information about nanomaterials characteristics like Abs max and λ max (Quevedo et al. 2021). Moreover, UV-Vis spectroscopy makes it possible to quantify the quantity of precursor metal ions needed to create metal nanoparticles (Sakthi and Saravanakumari 2021). According to theoretical predictions, MnO NPs should display an absorption peak in the range of 350—410 nm (Saod et al. 2022). UV-visible spectroscopy analysis of MnO NPs produced using basil extract revealed a maximum absorption at 405 nm (Boulaares et al. 2024c). For identifying the existence of distinct functional groups in nanomaterials, Fourier-transform infrared spectroscopy (FT-IR) is one of the most pertinent and frequently utilized analytical techniques (Sahib and Naser 2021). Metal-oxygen bond signatures generally exhibit absorption bands in the wavenumber range of 400—600 cm^—1 (Nayan et al. 2019). In the case of MnO NPs, FT-IR spectra revealed transmittance bands at 470 and 522 cm⁻¹, which are consistent with the expected range for Mn-O bonds (Boulaares et al. 2024c). Similarly, research by Sahib and Naser identified distinctive peaks at 493 and 524 cm⁻¹, further confirming the existence of Mn-O bonds (Sahib and Naser 2021). The surface morphology, distributed and agglomerated nanoparticles, and crystal form can all be seen using SEM with a secondary electron detector. SEM can also study individual particles, including the way they aggregate (Sakthi and Saravanakumari 2021). A study employing SEM revealed that the diameters of manganese oxide nanoparticles ranged from 30 to 40 nm (Sahib and Naser 2021). The primary purpose of the XRD is to examine the phase morphology of the NPs (Amatya et al. 2021). Consequently, it is a helpful method for determining the nanomaterials’ average crystallite size, phase composition, and crystal structure (Rehman et al. 2022). A study by Boulaares et al. (2024c) showed that the chemical composition of the manganese oxide nanoparticles was verified as Mn₃O₄ through XRD analysis, which corresponded to the JCPDS card Nº 00-001-1127 database. The particles exhibited a tetragonal crystallite structure with a size (D) of 13.4 nm, 23.09% crystallinity, and lattice parameters where a=b=6.202 Å and c=8.162 Å The XRD pattern displayed 9 distinct peaks at the following angles and corresponding planes: 18.02º (101), 29.07º (112), 32.66º (103), 36.11º (211), 38.42º (004), 44.40º (220), 55.88º (303), 60.20º (224), and 64.62º (314).

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BIOMEDICAL APPLICATIONS

Antioxidant Activity of MnO NPs

Changes in metabolism and physiology, as well as a number of diseases, are largely caused by oxidative stress (Chetehouna et al. 2020). Oxidative stress is caused by hydrogen peroxide (H₂O₂), which is created by vascular and inflammatory cells (Coyle and Kader 2007). Contrary to the abnormal ROS-generation mechanism, excess hydrogen peroxide (H₂O₂) might be consumed by manganese dioxide (MnO₂) nanoparticles and converted into O₂ in situ (Li et al. 2021). The idea presented by Ding et al. (2020) that MnO₂ catalyzes the breakdown of H₂O₂ into oxygen and water to reduce the oxidative stress reaction and give cells an oxygen equivalent was validated by Zhang et al. (2022). The generated MONPs exhibited strong antioxidant activity against DPPH free radical scavenging and were biocompatible (Kuthati et al. 2019). To assess the antioxidant capacity of MnO₂ NPs, 2-diphenyl-1-picrylhydrazyl (DPPH) free radicals were subjected to test materials at different doses (Faisal et al. 2022b).

Table 1. Green synthesis of manganese oxide nanoparticles using various plants.

Immunomodulatory Activity of MnO NPs

Inflammation is a global health issue that is triggered by microorganisms and irritants (Derouiche et al. 2022). There are a number of nanoparticle (NP) kinds that may have anti-inflammatory effects (Wang et al. 2021). Simultaneously, MnO₂ particles have the capability to modulate the synthesis of cytokines by controlling gene expression, thereby diminishing the extent of inflammation. Throughout this mechanism, MnO₂ undergoes gradual decomposition into Mn²⁺ ions, which are subsequently eliminated through bodily fluids, facilitating the restoration of the body’s internal milieu to an optimal condition (Zhang et al. 2022). Furthermore, the delivery of nanoparticles to inflammatory areas may be enhanced by immune cells (Mahdavi Gorabi et al. 2019). According to a study by Kumar et al. (2019b), manganese dioxide nanoparticles protect cartilage against oxidative stress caused by inflammation. Moreover, Li et al.’s research confirmed that using MnO₂ and fingolimod (FTY) together could have a synergistic neuroprotective impact on ischemic stroke patients by lowering oxidative stress and controlling the inflammatory microenvironment (Li et al. 2021).

Anti-Cancer Activity of MnO NPs

Cancer is a major public health concern throughout the world (Boulaares et al. 2024a) and the principal cause of mortality (Boulaares et al. 2020). Many different therapeutic techniques are being investigated in an effort to fight cancer (Boulaares et al. 2024b). Nanoparticles predominantly induce apoptosis in cancer cells through a series of pathways, with reactive oxygen species-mediated apoptosis being the most extensively explored. Apart from this, mechanisms such as immunological interventions, transcriptional inhibition, modulation of protein expression levels, and site-specific cytotoxicity, among others, also contribute to the stimulation of apoptosis in cancer cells by nanoparticles (Mundekkad and Cho 2022). Because of their size, the nanoparticles can more easily penetrate the tumor cell membrane (Das et al. 2023). According to Mahlangeni and Moodley (2021), MnOx NPs exhibited increasing cytotoxic effects on cancer cell lines at increasing doses while exhibiting no cytotoxicity toward normal cells. The findings of Majani et al. (2023) suggested that MnO₂ NPs, which are Phytosynthesized, may have anticancer properties since they significantly cytotoxically affect MCF-7 and MDA-MB-231 breast cancer cell lines. Sobañska et al. (2021) reported that another arena where Mn nanoparticles demonstrate their effectiveness is cancer therapy.

Anti-Diabetic Activity of MnO NPs

Research has demonstrated that manganese oxide nanoparticles exert a notable impact on the regulation of glucose levels in animal models with diabetes (Ali et al. 2024). As per Adeyemi et al. (2022), the demonstrated inhibitory effects of the fabricated Mn₃O₄ NPs possess the capacity to serve as a promising alternative treatment in the battle against diabetes. α-Amylase and α-glucosidase catalyze the hydrolysis of carbohydrates, resulting in the formation of disaccharides and oligosaccharides within the gastrointestinal tract. Consequently, this enzymatic activity contributes to the increase of glucose levels in the bloodstream, leading to the manifestation of hyperglycemia among individuals diagnosed with diabetes. The primary pharmacological approach in managing hyperglycemia involves the utilization of medications that specifically target these enzymes (Ramasubbu et al. 2023). The postulated mechanism responsible for the reduction in blood sugar levels induced by MnO₂ NPs is associated with the suppression of α-amylase and α-glucosidase enzymes, pivotal in the metabolism of carbohydrates (Farhan and Mohammed 2024). Ahmad and colleagues discovered that the assays for α-amylase and α-glucosidase revealed that manganese nanoparticles produced through green synthesis exhibit potential as an anti-diabetic treatment, with IC₅₀ values of 26.65 and 27.37 µg/ml, respectively (Ahmad et al. 2024).

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DISCUSSION

By relying on the attributes of manganese oxide nanoparticles enveloped by a shell of bioactive molecules derived from plants, alongside the considerations of biomedical utilization, numerous suggestions exist for therapeutic approaches involving manganese oxide nanoparticles to combat microbial infections. These approaches may involve the treatment of existing infections or the eradication of microorganisms preemptively prior to infection.

Metal and metal oxide nanoparticles are of interest for their antimicrobial properties. MnO₂ NPs are notable for their small size and unique characteristics, allowing them to penetrate microorganism cells easily. This penetration leads to a significant inhibition mechanism within the cells, causing distortions and destruction of cell membranes. Ultimately, this results in the death of microbial cells (Joshi et al. 2020a). The antimicrobial activity of Mn₃O₄ NPs is being studied. The ability of this nanomaterial to inhibit microbial growth is being considered for drug formulations in treating infectious diseases (Shaik et al. 2021). Several biologically derived nanoparticles (NPs) exhibited exceptional inhibition against multiple pathogenic microorganisms. Notably, some of these nanomaterials eliminated various microbial species that had developed resistance to available drugs (Singh et al. 2020).

Worldwide, bacterial infections remain to be a leading cause of death (Khan et al. 2020). According to the literature, metal or oxide particles smaller than 100 nm in size can easily penetrate the larger pores of bacterial cell membranes and interact with the bacteria. This can cause significant changes in physiological processes, leading to damage to the bacterial cell. Additionally, the death of the bacterial cell is thought to be due to the electrostatic interaction between the positively charged Mn NPs and the negatively charged cell membrane surface (Amatya and Shrestha 2021). The outcomes of the experiment demonstrate the effectiveness of MnO₂ NPs as antibacterial agents. Because MnO₂ NPs have the lowest size, their ability to readily penetrate bacterial cells and break their cell membranes determines their antibacterial activity (Joshi et al. 2020b). Research conducted by Wahran et al. revealed that the synergistic impact between antibiotics and MnO NPs is attributable to the nano size of the particles and their extensive surface area, allowing for easy incorporation and delivery of the antibiotic substances inside the cells. These substances are then distributed through the transfer channels and cell walls, leading to more efficient metabolite release (Saod et al. 2022). Additionally, Lu et al. (2022) reported that the antibacterial activity of MnO₂ NPs synthesized from Viola betonicifolia leaf extract indicated more than 80% killing efficiency in S. aureus and K. pneumoniae. MnO NPs produced from an extract of the leaves of Abutilon indicum showed strong antibacterial action against both Gram-positive and Gram-negative bacteria, according to (Hano and Abbasi 2022). A prior investigation revealed that MnO₂ nanoparticles had an antibacterial agent impact on bacteria with different inhibitory zone diameters, including S. aureus, E. coli, Klebsiella pneumonia, B. subtilis, and Pseudomonas aeruginosa (Ogunyemi et al. 2019).

MnO₂ NPs, acknowledged for their remarkable stability and capacity to elicit an immune response, are progressively being regarded as promising candidates in the domain of antiviral therapeutics (Baghban et al. 2024). The antiviral properties of the nanoparticles involve various mechanisms, including binding to the viral membrane to disrupt the DNA/RNA functions, entering host cells to dismantle their architecture, and producing reactive oxygen species (Gupta et al. 2022). Moreover, it has been illustrated that the Mn²⁺ discharged by MnO₂ NPs is crucial in modulating the immune response in the context of viral infections (Baghban et al. 2024).

Nanoparticles additionally fulfill an essential role as agents possessing antifungal properties (Dheeb et al. 2019). The research was conducted to examine the fungicidal efficacy of the nanoparticles, which culminated in an alteration of the fungal membrane (Shah et al. 2022). According to Faisal et al. (2022b) the antifungal activity values of MnO₂ nanoparticles, which were synthesized in an eco-friendly manner using Fagonia cretica, exhibited distinct measurements across various samples. Specifically, the recorded values were 14.2 ± 86, 8.9 ± 6.0, 17.7 ± 1.26, and 20.7 ± 4.38 mm for Penicillium expansum, Monilinia fructigena, Penicillium chrysogenum, and Aspergillus oryzae, respectively, at a concentration of 200 µg/well.

Given the ability of microorganisms like bacteria, viruses, fungi, and parasites to withstand and proliferate in the presence of drugs intended to eradicate them, manganese oxide nanoparticles are employed to combat various microbial-induced diseases. This approach addresses the issue of antimicrobial resistance in these microbes.

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CONCLUSION

As antioxidants and anti-inflammatory agents, manganese nanoparticles made from green materials such as plant, microbial, fungal, and algae extracts can be used in a variety of ways. Research on metal nanotherapies, such as MnO NPs, has been approved for a variety of infections, including those caused by bacteria, viruses, and fungi. MnO NPs gained notice because of their wide application in the pharmaceutical industry. Then, it might be discovered that these therapeutic approaches are helpful for other kinds of infectious disorders as well as for these particular bacterial infections. Because of the green synthesis’s ability to produce biocompatible compounds, these molecules may find utility in a variety of biomedical applications when toxicity is not a concern.

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ACKNOWLEDGMENTS

Not applicable.

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CONFLICT OF INTEREST

The authors state no conflicts of interest that could have influenced this work.

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FUNDING

None.

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AUTHORS’ CONTRIBUTIONS

B.I. prepared the initial manuscript. D.S. and B.I. were responsible for drafting and editing the final article. D.S. was the supervisor too. All authors have read and approved the final manuscript.

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DATA AVAILABILITY

All data are provided in the manuscript.

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